Field of the Invention
The invention relates to a 2-aminothiazole derivative represented by formula (I),
a preparation method thereof, and a method for using the same for the treatment of Alzheimer's disease (AD) by inhibiting acetylcholine esterase to inhibit apoptosis of nerve cells resulting from oxidative stresses, as well as a method for using the same for the treatment of anti-transplant rejection, anti-autoimmune disease, anti-ischemia-reperfusion injury, anti-chronic inflammation, and anti-endotoxaemia by inhibiting myeloid differential protein (MYD-88) to produce an immunosuppressive effect.
Description of the Related Art
Compounds containing 2-aminothiazole ring have been widely applied in anti-bacteria, anti-inflammation, and anti-allergy, and have been found in medicines of dopamine agonists, angiotensin receptor antagonists, and the like. However, applications of the compounds containing 2-aminothiazole ring in neurodegenerative diseases and kin immunosuppressant have been rarely reported.
AD is a neurodegenerative disorder based on the degeneration of primary neurons. Besides exceeding 7% of patients of 60 years of age and older have been tortured by AD, younger people trend to get AD. Thus, it has been a research hotspot in medical filed to develop an effective medicine for curing AD and other neurodegenerative disorders.
A plurality of factors account for the AD. Low activity of choline acetyltransferase and low Choline uptake capacity results in dysfunction of neurite transfer and that neurons or glial cells are incapable of providing sufficient nutrients, thereby leading to functional degradation of subcutaneous neuron system. Overactivity of glutamate receptor, high level of reactive oxygen (oxidative stresses), inflammation, and virus infection result in impaired metabolic pathways, and lowered energy production in mitochondria. In the presence of β-secretase and γ-secretase, β-amyloid precursor protein (APP) is transformed into β-amyloid (Aβ), which leads to amyloid agglomeration. Abnormal phosphorylation of Tau protein leads to tangles of nerve fibers and DNA and RNA mutations in nucleus or mitochondria.
Currently, the treatment of the AD is based on the control of the cause of disease and the symptom, including: improving the cognitive ability of patients, and weakening the functional degradation of subcutaneous neuron system. For example, using cholinoceptor agonists or acetylcholinesterase inhibitors (such as Aricept, Tacrine, and Donepezil) to increase the acetylcholine in vivo to improve the cognitive ability; and using medicines like calcium antagonist Nimodipine that is capable of lowering the free radicals (such as VE and Selegiline) and avoiding intracellular calcium overload to weaken the degradation of the neurons and the synapses. These means have some improvement during the treatment of early AD. However, neither acetylcholinesterase inhibitors nor other medicines have ideal clinical effects.
Although a plurality of regulatory factors induce neuronal apoptosis, principals of medicines for inhibiting of rapid degradation of nerve cells focus on either removing cell apoptosis signals to inhibit the initiation of cell apoptosis, or inhibiting cascade reaction after the initiation of the cell apoptosis. Non-histone chromosomal proteins poly (ADP-ribose) poly-merase (PARP) existing in eucaryotic cells are capable of regulating cellular process including DNA repair and maintenance of genomic stability, regulatory of transcription to regulating protein expression levels, and influence on replication and differentiation. The inhibition of PARP is capable of not only decreasing the impact on organs from inflammation, but also lowering the neural excitotoxicity of NMDA and KA. Thus, the inhibition of PARP protects the never cells, thereby being widely concerned in treatment of neurodegenerative diseases, nerve inflammation, and cerebral ischemia.
AD is a kind of multi-factorial diseases, and cannot be cured by single-targeted medicines. A combination of drugs is used in treatment, and advantages of multi-targeted drugs have been concerned. So far, inhibitors, such as ladostigil and rivastigmine, which can simultaneously act on Ache and brain MAO inhibitors, have been designed in accordance with the principal of the drug combination.
Besides, endogenous and exogenous risk factors stimulate each TLR of the innate immune system, stimulate signal transfer by key molecule myeloid differentiation protein 88 (MyD88), and activate NF-B and corresponding immune responses. Thus, MyD88 is a key molecule for the innate immune system. To inhibit the My88 is to inhibit the main reaction in the innate immune system and to achieve corresponding immunosuppressive effect. Because MyD88 is a new immunosuppressive target itself and available MyD88 inhibitors are mainly peptidomimetic compound or small molecules of complex structure, the preparation of MyD88 inhibitors are difficult and have high production cost, thereby being difficult to popularize in clinical treatment.